Arylkylamine spirofuropyridines useful in therapy

ABSTRACT

A compound of formula I,  
                 
 
     wherein NRR 1  is attached at the 5- or 6-position of the furopyridine ring; R is hydrogen, C 1 -C 4  alkyl, or COR 2 ; R 1  is (CH 2 ) n Ar, CH 2 CH═CHAr, or CH 7 C≡CAr; n is 0 to 3; A is N or NO; Ar is a 5- or 6-membered aromatic or heteroaromatic ring which contains zero to four nitrogen atoms, zero to one oxygen atoms, and zero to one sulfur atoms; or an 8-, 9- or 10-membered fused aromatic or heteroaromatic ring system containing zero to four nitrogen atoms, zero to one oxygen atoms, and zero to one sulfur, any of which may optionally be substituted with one to two substitutents independently selected from: halogen, trifluoromethyl, or C 1 -C 4  alkyl; R 2  is hydrogen, C 1 -C 4  alky, C 1 -C 4  alkoxy or phenyl ring optionally substituted with one to three of the following substituents: halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, OH; OC 1 -C 4  alkyl, CO 2 R 5 , —CN, —NO 2 , —NR 3 R 4 , or —CF 3 ; R 3 , R 4  and R 5  may be hydrogen, C 1 -C 4  alkyl, or phenyl ring optionally substituted with one to three of the following substituents: halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, OH; OC 1 -C 4  alkyl, —CN, —NO 2 , or —CF 3 ; and enantiomers thereof, and pharmaceutically acceptable salts thereof, processes for preparing them, composition containing them, and their use in therapy, especially in the treatment or prophylaxis of psychotic disorders and intellectual impairment disorders.

TECHNICAL FIELD

[0001] This invention relates to novel substituted amines ofspirofuropyridines or pharmaceutically acceptable salts thereof,processes for preparing them, pharmaceutical compositions containingthem and their use in therapy. A further object is to provide activecompounds, which are potent ligands for nicotinic acetylcholinereceptors (nAChR's).

BACKGROUND OF THE INVENTION

[0002] The use of compounds which bind nicotinic acetylcholine receptorsin the treatment of a range of disorders involving reduced cholinergicfunction such as Alzheimer's disease, cognitive or attention disorders,anxiety, depression, smoking cessation, neuroprotection, schizophrenia,analgesia, Tourette's syndrome, and Parkinson's disease has beendiscussed in McDonald et al. (1995) “Nicotinic Acetylcholine Receptors:Molecular Biology, Chemistry and Pharmacology”, Chapter 5 in AnnualReports in Medicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc.,San Diego, Calif.; Williams et al. (1994) “Neuronal NicotinicAcetylcholine Receptors,” Drug News & Perspectives, vol. 7, pp. 205-223;and Lin and Meyer, “Recent Developments in Neuronal NicotinicAcetylcholine Receptor Modulators”, Exp. Opin. Ther. Patents. (1998),8(8): 991-1015.

[0003] U.S. Pat. No. 5,468,875 discloses N-alkylcarbamic acid1-azabicyclo[2.2.1]hept-3-yl esters which are centrally activemuscarinic agents useful in the treatment of Alzheimer's disease andother disorders.

[0004] N-(2-alkoxyphenyl) carbamic acid 1-azabicyclo[2.2.2]octan-3-ylesters are disclosed in Pharmazie, vol. 48, 465-466 (1993) along withtheir local anesthetic activity. N-phenylcarbamic acid1-azabicyclo[2.2.2]octan-3-yl esters substituted at the ortho positionon the phenyl ring are described as local anaesthetics in Acta Pharm.Suecica, 7, 239-246 (1970).

[0005] Furopyridines useful in controlling synaptic transmission aredisclosed in WO 97/05139.

DISCLOSURE OF THE INVENTION

[0006] According to the invention it has been found that compounds offormula I,

[0007] wherein

[0008] NRR₁ is attached at the 5- or 6-position of the furopyridinering;

[0009] R is hydrogen, C₁-C₄ alkyl, COR₂;

[0010] R₁ is (CH₂)_(n)Ar, CH₂CH═CHAr, or CH₂C≡CAr;

[0011] n is 0 to 3;

[0012] A is N or NO;

[0013] Ar is a 5- or 6-membered aromatic or heteroaromatic ring whichcontains zero to four nitrogen atoms, zero to one oxygen atoms, and zeroto one sulfur atoms;

[0014] or an 8-, 9- or 10-membered fused aromatic or heteroaromatic ringsystem containing zero to four nitrogen atoms, zero to one oxygen atoms,and zero to one sulfur atoms; any of which may optionally be substitutedwith one to two substitutents independently selected from: halogen,trifluoromethyl, or C₁-C₄ alkyl;

[0015] R₂ is hydrogen, C₁-C₄ alkyl; C₁-C₄ alkoxy; or phenyl ringoptionally substituted with one to three of the following substituents:halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, OH; OC₁-C₄ alkyl,CO₂R₅, —CN, —NO₂, —NR₃R₄, or —CF₃;

[0016] R₃, R₄ and R₅ are independently hydrogen; C₁-C₄ alkyl; or phenylring optionally substituted with one to three of the followingsubstituents: halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, OH,OC₁-C₄ alkyl, CO₂R₂, —CN; —NO₂, or —CF₃;

[0017] or an enantiomer thereof, and pharmaceutically acceptable saltsthereof, are potent ligands for nicotinic acetylcholine receptors.

[0018] Unless otherwise indicated, the C₁-C₄ alkyl groups referred toherein, e.g., methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl,t-butyl, s-butyl, may be straight-chained or branched, and the C₃-C₄alkyl groups may also be cyclic, e.g., cyclopropyl, cyclobutyl.

[0019] Unless otherwise indicated, the C₁-C₄ alkoxy groups referred toherein, e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,t-butoxy, s-butoxy, may be straight-chained or branched.

[0020] Unless otherwise indicated, the C₂-C₄ alkenyl groups referred toherein may contain one or two double bonds, e.g., ethenyl, i-propenyl,n-butenyl, i-butenyl, allyl, 1,3-butadienyl.

[0021] Unless otherwise indicated, the C₂-C₄ alkynyl groups referred toherein contain one triple bond, e.g., ethynyl, propynyl, 1- or2-butynyl.

[0022] Halogen referred to herein may be fluoride, chloride, bromide, oriodide.

[0023] Unless otherwise indicated, (subst)phenyl refers to a phenyl ringoptionally substituted with one to three of the following substituents:hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, OH, OC₁-C₄alkyl, CO₂R₅, —CN, —NO₂, —NR₃R₄, —CF₃.

[0024] Preferred compounds of the invention are compounds of formula Iwherein A is N.

[0025] Preferred compounds of the invention are compounds of formula Iwherein R₁ is (CH₂)_(n)Ar.

[0026] Preferred compounds of the invention are compounds of formula Iwherein R₁ is CH₂CH═CHAr.

[0027] Preferred compounds of the invention are compounds of formula Iwherein R₁ is CH₂C≡CAr.

[0028] Preferred compounds of the invention are compounds of formula Iwherein Ar is selected from the group: phenyl ring optionallysubstituted with one to three of the following substituents: halogen,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, OH, OC₁-C₄ alkyl, CO₂R₅, —CN,—NO₂, —NR₃R₄, and —CF₃; 2-, 3-, or 4-pyridyl; 2-, or 3-furanyl; 2-, or3-thienyl; 2-, or 4-imidazolyl; 1, 2-, or 3-pyrrolyl; 2-, or 4-oxazolyl;and 3-, or 4-isoxazolyl.

[0029] Preferred compounds of the invention are compounds of formula Iwherein Ar is selected from the group: 1-, or 2-naphthyl; 2-, 3-, 4-,5-, 6-, 7-, or 8-quinolyl; 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl; 2-,4-, 5-, 6-, or 7-benzoxazolyl; and 3-, 4-, 5-, 6-, or 7-benzisoxazolyl.

[0030] Preferred compounds of the invention are compounds of formula I,wherein R₃, R₄ and R₅ are independently hydrogen, or C₁-C₄ alkyl.

[0031] Preferred compounds of the invention are compounds of formula Iwherein n is 1.

[0032] Preferred compounds of the invention are compounds of formula Iwherein R is hydrogen.

[0033] Preferred compounds of the invention are compounds of formula Iwherein Ar is an heteroaromatic ring.

[0034] Preferred compounds of the invention are compounds of formula Iwherein n is 1, R is hydrogen and Ar is an heteroaromatic ring.

[0035] Preferred compounds of the invention include the following:

[0036]R-(−)-5′-N-(Phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0037]R-(−)-5′-(2-Pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0038]R-(−)-5′-(3-Pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0039]R-(−)-5′-(4-pPyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0040]R-(−)-5′-(2-Furanylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0041]R-(−)-5′-(3-Furanylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0042]R-(−)-5′-(2-Thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0043]R-(−)-5′-(2-Imidazolylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0044]R-(−)-5′-N-(4-Methoxyphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0045]R-(−)-5′-N-(4-Chlorophenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0046]R-(−)-5′-N-(4-Methylphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0047]R-(−)-5′-N-(3,4-Dichlorophenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0048]R-(−)-5′-N-Acetyl-N-(phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0049]R-(−)-5′-N-Methyl-N-(phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0050]R-(−)-5′-N-(3-Pyridyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];

[0051]R-(−)-6′-N-(Phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];

[0052]R-(−)-5′-N-(3-Thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0053]R-(−)-5′-N-(2-Phenylethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0054]R-(−)-5′-N-(3-Phenylpropyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0055]R-(−)-5′-N-(Quinolin-3-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0056]R-(−)-5′-N-(Quinolin-4-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0057]R-(−)-5′-N-(1,4-Benzodioxan-6-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0058]R-(−)-5′-N-(Imidazol-4-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0059]R-(−)-5′-N-(trans-3-Phenylprop-2-enyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0060]R-(−)-5′-N-(Thiazol-2-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0061]R-(−)-5′-N-(3-Methylphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0062]R-(−)-5′-N-(2-Chlorophenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0063]R-(−)-5′-N-(3-Chlorophenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0064]R-(−)-5′-N-(3-Phenylpropynyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0065]R-(−)-5′-N-(3-Hydroxyphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0066]R-(−)-5′-N-(4-Hydroxyphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0067]R-(−)-5′-N-[trans-3-(4-Pyridinyl)prop-2-enyl]aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0068]R-(−)-5′-N-Acetyl-N-(3-Thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0069]R-(−)-5′-N-Methyl-N-(4-pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0070]R-(−)-5′-N-Methyl-N-(3-pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0071]R-(−)-5′-N-(2-Hydroxyethyl)-N-(3-thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0072] and enantiomers thereof, and pharmaceutically acceptable saltsthereof.

[0073] Particularly preferred compounds of the invention are compoundsof formula I wherein n is 1; R is hydrogen and Ar is an heteroaromaticring, including the following compounds:

[0074]R-(−)-5′-(3-Pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0075]R-(−)-5′-(4-Pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

[0076] and enantiomers thereof, and pharmaceutically acceptable saltsthereof.

[0077] The compounds of the invention have the advantage that they maybe less toxic, be more efficacious, be longer acting, have a broaderrange of activity, be more potent, produce fewer side effects, are moreeasily absorbed or have other useful pharmacological properties.

[0078] Methods of Preparation

[0079] In the reaction schemes and text that follow, R and R₁, unlessotherwise indicated, are as defined above for formula I. Formula VIIIrepresents a compound of formula I wherein NRR₁ is attached at the5-position of the furopyridine ring. Formula IX represents a compound offormula I wherein NRR₁ is attached at the 6-position of the furopyridinering. A represents N; E represents halogen, NO₂, or NHR. The compoundsof formula I may be prepared according to the methods outlined in Scheme1.

[0080] Compounds of formula I wherein A represents NO may be preparedfrom compounds of formula I wherein A represents N by oxidation with aperoxidic reagent in a suitable solvent, followed by reduction of thetertiary amine oxides in a suitable solvent. Oxidizing agents includehydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, or magnesiummonoperoxyphthalate. The preferred oxidant is m-chloroperbenzoic acid.Suitable inert solvents include chloroform, methylene chloride, and1,2-dichloroethane. The preferred solvent is dichloromethane. Thereaction is usually conducted at a temperature from −20° C. to 66° C.,preferably from 0° C. to 20° C. Reducing agents include sulfur dioxideand triphenylphosphine. The preferred reagent is sulfur dioxide.Suitable inert solvents include water and alcohols. The preferredsolvent is ethanol. The reaction is usually conducted at a temperaturefrom −20° C. to 50° C., preferably from 0° C. to 25° C.

[0081] Compounds of formula I wherein R represents COR₂ may be preparedfrom compounds of formula I wherein R represents hydrogen using asuitable acylation procedure. Typical acylation procedures includetreatment with a carboxylic acid and a coupling agent, for exampledicyclohexylcarbodiimide, in a suitable solvent, for exampletetrahydrofuran, or treatment with a carboxylic acid chloride oranhydride in the presence of a base. The preferred method is treatmentwith a carboxylic anhydride. Suitable bases include triethylamine,4-(N,N-dimethylamino)pyridine, or pyridine. The preferred base ispyridine. The reaction is usually conducted at a temperature of 0° C. to120° C., preferably from 80° C. to 100° C.

[0082] Compounds IX may be prepared from compound VII by reaction with ahalogenating reagent such as phosphorus oxychloride, phosphorusoxybromide, phosphorus pentachloride or phosphorus pentabromide,followed by reaction with an amine in an inert solvent. The preferredhalogenating agent is phosphorus oxychloride. The halogenating reactionis usually conducted at a temperature from 0° C. to 150° C., preferablyfrom 80° C. to 120° C. The amine component may be any amine NHRR₁defined as above. Suitable inert solvents include alcoholic solventssuch as methanol and ethanol, as well as aromatic solvents such asbenzene, toluene or xylene. The preferred inert solvent is ethanol. Thereaction is usually conducted at a temperature from 20° C. to 200° C.,preferably from 100° C. to 170° C. The reaction with the amine may befacilitated by the presence of a suitable organometallic catalyst and abase. Suitable organometallic catalysts include palladium phosphinecomplexes, which may be formed in situ from a source of palladium and asuitable phosphine. The preferred source of palladium istris(dibenzylidineacetone)dipalladium (0). The preferred phosphine is2-2′-bis(diphenylphosphino)1,1′-binaphthyl. Suitable bases includelithium bis(trimethylsilyl)amide, or sodium t-butoxide, preferablysodium t-butoxide. Suitable inert solvents for the reaction in thepresence of an organometallic catalyst include tetrahydrofuran,1,2-dimethoxyethane, or 1,4-dioxane, preferably 1,2-dimethoxyethane, andthe reaction is usually conducted at a temperature of 60° C. to 120° C.,preferably from 80° C. to 110° C.

[0083] Compounds of formula VIII may be prepared from compounds offormula VI wherein E represents NHR by a suitable alkylation procedure.Typical alkylation procedures include treatment with an appropriatealkyl halide or sulfonate ester and base, for example sodium hydride, ina suitable solvent, for example DMF, or reductive alkylation using theappropriate aromatic aldehyde together with a suitable reducing agent inan inert solvent. The preferred method is reductive alkylation. Suitablearomatic aldehydes include Ar(CH₂)_(m)CHO, ArCH═CHCHO, or ArC≡CCHO,where m may be 0-2 and Ar is defined as above. Suitable reductivealkylating agents include sodium borohydride and sodiumcyanoborohydride. The preferred reducing agent is sodium borohydride.Suitable inert solvents include water, methanol or ethanol. Thepreferred solvent is methanol. The reaction is usually conducted at atemperature of 0° C. to 100° C., preferably from 20° C. to 65° C.

[0084] Compounds of formula VIII may be prepared from compounds offormula VI wherein E represents halogen by reaction with an amine offormula RR₁NH in the presence of a suitable organometallic catalyst,base, and solvent. Suitable organometallic catalysts include palladiumphosphine complexes, which may be formed in situ from a source ofpalladium and a suitable phosphine. The preferred source of palladium istris(dibenzylidineacetone)dipalladium (0). The preferred phosphine is2-2′-bis(diphenylphosphino)1,1′-binaphthyl. Suitable bases includelithium bis(trimethylsilyl)amide, or sodium t-butoxide, preferablysodium t-butoxide. Suitable inert solvents include tetrahydrofuran,1,2-dimethoxyethane, or 1,4-dioxane. The preferred solvent is1,2-dimethoxyethane. The reaction is usually conducted at a temperatureof 60° C. to 120° C., preferably from 80° C. to 110° C.

[0085] Compound VII may be prepared from compound V by oxidation with aperoxidic reagent in a suitable solvent, followed by reduction of thetertiary amine oxides in a suitable solvent. Oxidizing agents includehydrogen peroxide, m-chloroperbenzoic acid peracetic acid, or magnesiummonoperoxyphthalate. The preferred oxidant is m-chloroperbenzoic acid.Suitable inert solvents include chloroform, methylene chloride, and1,2-dichloroethane. The preferred solvent is dichloromethane. Thereaction is usually conducted at a temperature from −20° C. to 66° C.,preferably from 0° C. to 20° C. Reducing agents include sulfur dioxideand triphenylphosphine. The preferred reagent is sulfur dioxide.Suitable inert solvents include water and alcohols. The preferredsolvent is ethanol. The reaction is usually conducted at a temperaturefrom −20° C. to 50° C., preferably from 0° C. to 25° C.

[0086] Compounds of formula VI wherein E represents NHR and R representsan alkyl group may be prepared from compounds of formula VI wherein Erepresents NH₂ by a suitable alkylation procedure. Typical alkylationprocedures include treatment with an appropriate alkyl halide orsulfonate ester and base, for example sodium hydride, in a suitablesolvent, for example DMF, or reductive alkylation using the appropriatealdehyde or ketone together with a suitable reducing agent in an inertsolvent. The preferred method is reductive alkylation. Suitable reducingagents include sodium borohydride and sodium cyanoborohydride. Thepreferred reducing agent is sodium borohydride. Suitable inert solventsinclude water, methanol or ethanol. The preferred solvent is methanol.The reaction is usually conducted at a temperature of 0° C. to 100° C.,preferably from 20° C. to 65° C.

[0087] Compounds of formula VI wherein E represents NH₂ may be preparedfrom compounds of formula VI wherein E represents NO₂ by reduction in asuitable solvent. Suitable reducing agents include hydrogen in thepresence of a catalyst, for example 5-10% palladium on carbon, platinumoxide, or rhodium on carbon. The preferred reducing agent is hydrogen inthe presence of 10% palladium on carbon. Suitably inert solvents includewater, methanol or ethanol. The preferred solvent is methanol. Thereaction is usually conducted at a temperature of 0° C. to 65° C.,preferably 15° C. to 30° C.

[0088] Compound VI wherein E represents NO₂ may be prepared fromcompound V by reaction with a nitrating agent in an appropriate solvent.The preferred nitrating agent is fuming nitric acid; the preferredsolvent is sulfuric acid. The reaction is usually conducted at atemperature from −10° C. to 100° C., preferably from 50° C. to 80° C.

[0089] Compounds of formula VI wherein E represents halogen may beprepared from a compound V by reaction with a halogenating agent in asuitable solvent, for example bromine in acetic acid. The reaction isusually carried out at a temperature of 0° C. to 110° C., preferablyfrom 60° C. to 110° C.

[0090] Compound V may be prepared from the cyclization of compound IV inthe presence of a base in an inert solvent, followed by deprotection ofthe cyclized compound using acid in a suitable solvent. Suitable basesinclude sodium hydride, sodium amide, potassium hydride, potassiumt-amylate, potassium t-butoxide, and potassium bis(trimethylsilyl)amide.The preferred base is sodium hydride. Suitable inert solvents includeN,N-dimethylformamide, N-methylpyrrolidin-2-one, ethers such as diethylether, tetrahydrofuran, and 1,4-dioxane, and dimethylsulfoxide. Thepreferred inert solvent is N,N-dimethylformamide. The reaction isusually conducted at a temperature from −10° C. to 100° C., preferablyfrom 20° C. to 66° C.

[0091] Suitable acids for the deprotection of the cyclized compoundinclude mineral, organic and Lewis acids, for example, hydrochloric andhydrobromic acid, sulfuric acid, triflic acid, methanesulfonic acid, andboron trifluoride etherate. The preferred acid is hydrobromic acid.Suitable solvents include acetone, butanone, ethanone, and pinacolone.The preferred solvent is acetone. The reaction is usually conducted at atemperature from −10° C. to 100° C., preferably from 0° C. to 60° C.Alternatively the deprotection may be conducted by heating the boranecomplex in alcoholic solvents. A preferred method is by refluxing anethanolic solution of the complex.

[0092] Compound IV may be prepared from compound III using a lithiumbase and a proton transfer agent in an inert solvent. Suitable lithiumbases include lithium diisopropylamine n-butyllithium, sec-butyllithium,tert-butyllithium, and phenyllithium. The preferred lithium base isphenyllithium. Suitable proton transfer agents include hinderedsecondary amines such as diisopropylamine and2,2,6,6-tetramethylpiperidine. The preferred proton transfer agent isdiisopropylamine. Suitable inert solvents include diethyl ether,tetrahydrofuran and 1,4-dioxane. The preferred inert solvent istetrahydrofuran. The reaction is usually conducted at a temperature from−100° C. to 0° C., preferably from −78° C. to −25° C.

[0093] Compound III may be prepared from the reaction of compound IIwith an anion of a reagent well known in the art for the preparation ofoxiranes from ketones (see e.g. the reactions referenced in J. March,“Advanced Organic Chemistry” (1992) 4^(th) Edition, pages 974-975),followed by reaction with borane (BH₃ or B₂H₆) in an inert solvent,Borane in tetrahydrofuran is preferred. Suitable inert solvents includediethyl ether, tetrahydrofuran and 1,4-dioxane. The preferred inertsolvent is tetrahydrofuran. The reaction is usually conducted at atemperature from −10° C. to 66° C., preferably from 0° C. to 20° C.Suitable epoxidizing agents include trimethylsulfoxonium iodide,trimethylsulfonium iodide and diazomethane. The preferred reagent istrimethylsulfoxonium iodide. Suitable inert solvents include dipolaraprotic solvents. The preferred solvent is dimethylsulfoxide. Thereaction is usually conducted at a temperature from −10° C. to 100° C.,preferably from 50° C. to 75° C.

[0094] Where necessary, hydroxy, amino, or other reactive groups may beprotected using a protecting group as described in the standard text“Protecting groups in Organic Synthesis”, 2^(nd) Edition (1991) byGreene and Wuts.

[0095] The above described reactions, unless otherwise noted, areusually conducted at a pressure of one to three atmospheres, preferablyat ambient pressure (about one atmosphere). Unless otherwise stated, theabove-described reactions are conducted under an inert atmosphere,preferably under a nitrogen atmosphere.

[0096] The compounds of the invention and intermediates may be isolatedfrom their reaction mixtures by standard techniques.

[0097] Acid addition salts of the compounds of formula I which may bementioned include salts of mineral acids, for example the hydrochlorideand hydrobromide salts; and salts formed with organic acids such asformate, acetate, maleate, benzoate, tartrate, and fumarate salts.

[0098] Acid addition salts of compounds of formula I may be formed byreacting the free base or a salt, enantiomer or protected derivativethereof, with one or more equivalents of the appropriate acid. Thereaction may be carried out in a solvent or medium in which the salt isinsoluble or in a solvent in which the salt is soluble, e.g., water,dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture ofsolvents, which may be removed in vacuum or by freeze drying. Thereaction may be a metathetical process or it may be carried out on anion exchange resin.

[0099] The compounds of formula I exist in tautomeric or enantiomericforms, all of which are included within the scope of the invention. Thevarious optical isomers may be isolated by separation of a racemicmixture of the compounds using conventional techniques, e.g. fractionalcrystallization, or chiral HPLC. Alternatively the individualenantiomers may be made by reaction of the appropriate optically activestarting materials under reaction conditions which will not causeracemization.

[0100] Intermediates

[0101] A further aspect of the invention relates to new intermediates.Special interest among these new intermediates are the compounds offormula VI and VII in Scheme I. These intermediates are useful in thesynthesis of compounds of formula I, but their use is not limited to thesynthesis of said compounds. The formulas for these compounds arepresented below: Compounds of formula VI

[0102] where E is NO₂, NHR or halogen;

[0103] and compounds of formula VII

[0104] Intermediate compounds also exist in enantiomeric forms and maybe used as purified enantiomers, racemates or mixtures.

[0105] Is Use of compounds VI and VII as intermediates in a synthesis ofa ligand for nicotinic acetylcholine receptors is another aspect of theinvention.

[0106] Pharmaceutical Compositions

[0107] A further aspect of the invention relates to a pharmaceuticalcomposition for treating or preventing a condition or disorder asexemplified below arising from dysfunction of nicotinic acetylcholinereceptor neurotransmission in a mammal, preferably a human, comprisingan amount of a compound of formula I, an enantiomer thereof, and apharmaceutically acceptable salt thereof, effective in treating orpreventing such disorder or condition and an inert pharmaceuticallyacceptable carrier.

[0108] For the above-mentioned uses the dosage administered will, ofcourse, vary with the compound employed, the mode of administration andthe treatment desired. However, in general, satisfactory results will beobtained when the compounds of the invention are administered at a dailydosage of from 0.1 mg to 20 mg per kg of mammalian body weight,preferably given in divided doses 1 to 4 times a day or in sustainedrelease form. For man, the total daily dose is in the range of from 5 mgto 1,400 mg, more preferably from 10 mg to 100 mg, and unit dosage formssuitable for oral administration comprise from 2 mg to 1,400 mg of thecompound admixed with a solid or liquid pharmaceutical carrier ordiluent.

[0109] The compounds of formula I, or an enantiomer thereof, andpharmaceutically acceptable salts thereof, may be used on their own orin the form of appropriate medicinal preparations for enteral,parenteral, oral, rectal or nasal administration. According to a furtheraspect of the invention, there is provided a pharmaceutical compositionpreferably comprising less than 80% and more preferably less than 50% byweight of a compound of the invention in admixture with an inertpharmaceutically acceptable diluent or carrier.

[0110] Examples of suitable diluents and carriers are:

[0111] for tablets and dragees: lactose, starch, talc, stearic acid; forcapsules: tartaric acid or lactose;

[0112] for injectable solutions: water, alcohols, glycerin, vegetableoils; for suppositories: natural or hardened oils or waxes.

[0113] There is also provided a process for the preparation of such apharmaceutical composition, which comprises mixing the ingredientssimultaneously or sequentially.

[0114] Utility

[0115] A further aspect of the invention is the use of a compoundaccording to the invention, or an enantiomer thereof, and apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment or prophylaxis of one of the belowmentioned diseases or conditions; and a method of treatment orprophylaxis of one of the below mentioned diseases or conditions, whichcomprises administering a therapeutically effective amount of a compoundaccording to the invention, or an enantiomer thereof, and apharmaceutically acceptable salt thereof, to a patient.

[0116] Compounds according to the invention are agonists of nicotinicacetylcholine receptors. While not being limited by theory, it isbelieved that agonists of the α7 nAChR (nicotinic acetylcholinereceptor) subtype should be useful in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders, and haveadvantages over compounds which are, or are also agonists of the α4nAChR subtype. Therefore, compounds which are selective for the α7 nAChRsubtype are preferred. The compounds of the invention are selective forthe α7 nAChR subtype. The compounds of the invention are intended aspharmaceuticals, in particular in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders. Examples ofpsychotic disorders include schizophrenia, mania or manic depression,and anxiety. Examples of intellectual impairment disorders includeAlzheimer's disease, learning deficit, cognition deficit, attentiondeficit, memory loss, Lewy Body Dementia, and Attention DeficitHyperactivity Disorder. The compounds of the invention may also beuseful as analgesics in the treatment of pain (including chronic pain)and in the treatment or prophylaxis of Parkinson's disease, Huntington'sdisease, Tourette's syndrome, and neurodegenerative disorders in whichthere is loss of cholinergic synapses. The compounds may further beindicated for the treatment or prophylaxis of jetlag, for use ininducing the cessation of smoking, and for the treatment or prophylaxisof nicotine addiction (including that resulting from exposure toproducts containing nicotine).

[0117] It is also believed that compounds according to the invention areuseful in the treatment and prophylaxis of ulcerative colitis.

[0118] Pharmacology

[0119] The pharmacological activity of the compounds of the inventionmay be measured in the tests set out below:

[0120] Test A—Assay for Affinity at α7 nAChR Subtype

[0121]¹²⁵I-α-Bungarotoxin (BTX) binding to rat hippocampal membranes.Rat hippocampi were homogenized in 20 volumes of cold homogenizationbuffer (HB: concentrations of constituents (mM):tris(hydroxymethyl)aminomethane 50; MgCl₂ 1; NaCl 120; KCl 5: pH 7.4).The homogenate was centrifuged for 5 minutes at 1000×g, the supernatantwas saved and the pellet re-extracted. The pooled supernatants werecentrifuged for 20 minutes at 12,000×g, washed, and resuspended in HB.Membranes (30-80 μg) were incubated with 5 nM [¹²⁵I]α-BTX, 1 mg/mL BSA(bovine serum albumin), test drug, and either 2 mM CaCl₂ or 0.5 mM EGTA[ethylene glycol-bis(β-aminoethylether)] for 2 hours at 21° C., and thenfiltered and washed 4 times over Whatman glass fibre filters (thicknessC) using a Brandel cell harvester. Pretreating the filters for 3 hourswith 1% (BSA/0.01% PEI (polyethyleneimine)) in water was critical forlow filter blanks (0.07% of total counts per minute). Nonspecificbinding was described by 100 μM (−)-nicotine, and specific binding wastypically 75%.

[0122] Test B—Assay for Affinity to the α4 nAChR Subtype

[0123] [³H]-(−)-nicotine binding. Using a procedure modified fromMartino-Barrows and Kellar (Mol Pharm (1987) 31:169-174), rat brain(cortex and hippocampus) was homogenized as in the [¹²⁵I]α-BTX bindingassay, centrifuged for 20 minutes at 12,000×g, washed twice, and thenresuspended in HB containing 100 μM diisopropyl fluorophosphate. After20 minutes at 4° C., membranes (approximately 0.5 mg) were incubatedwith 3 nM [3H]-(−)-nicotine, test drug, 1 μM atropine, and either 2 mMCaCl₂ or 0.5 mM EGTA for 1 hour at 4° C., and then filtered over Whatmanglass fibre filters (thickness C) (pretreated for 1 hour with 0.5% PEI)using a Brandel cell harvester. Nonspecific binding was described by 100μM carbachol, and specific binding was typically 84%.

[0124] Binding Data Analysis for Tests A and B

[0125] IC₅₀ values and pseudo Hill coefficients (n_(H)) were calculatedusing the non-linear curve fitting program ALLFIT (DeLean A, Munson P Jand Rodbard D (1977) Am. J. Physiol., 235:E97-E102). Saturation curveswere fitted to a one site model, using the non-linear regression programENZFITTER (Leatherbarrow, R. J. (1987)), yielding K_(D) values of 1.67and 1.70 nM for the ¹²⁵I-α-BTX and [³H]-(−)-nicotine ligandsrespectively. K_(i) values were estimated using the generalCheng-Prusoff equation:

K_(i)-[IC₅₀]/((2+([ligand]/[K_(D)])^(n))^(1/n)−1)

[0126] where a value of n=1 was used whenever n_(H)<1.5 and a value ofn=2 was used when n_(H)≧1.5. Samples were assayed in triplicate and weretypically ±5%. K_(i) values were determined using 6 or more drugconcentrations. The compounds of the invention are compounds withbinding affinities (K_(i)) of less than 1000 nM in either Test A or TestB, indicating that they are expected to have useful therapeuticactivity.

EXAMPLES

[0127] Commercial reagents were used without further purification. Massspectra were recorded using either a Hewlett Packard 5988A or aMicroMass Quattro-1 Mass Spectrometer and are reported as m/z for theparent molecular ion with its relative intensity. Room temperaturerefers to 20-25° C.

[0128] The following examples are preferred non-limiting examplesembodying preferred aspects of the invention.

Preparation 1 Spiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane]N-boraneComplex (Compound III)

[0129] A mixture of trimethylsulfoxonium iodide (16.10 g, 73.2 mmol) anda dispersion of sodium hydride (60% in oil, 3.00 g, 75.0 mmol) inanhydrous dimethyl sulfoxide was stirred at room temperature undernitrogen for 30 minutes. Quinuclidin-3-one (II) (7.05 g, 56.3 mmol) wasthen added as a solid portionwise, and the resulting mixture was stirredat 65-70° C. under nitrogen for 1 hour. The reaction mixture was cooled,water was added (200 ml), and the resulting solution was extracted withchloroform (3×200 ml). The chloroform extracts were combined, andback-extracted with water (4×200 ml). The chloroform layer was thendried (MgSO₄), filtered, and evaporated under reduced pressure to affordspiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] (6.51 g, 46.8 mmol, 83%)as a clear, colorless liquid. To a stirred solution ofspiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] (5.3 g, 38.1 mmol) inanhydrous tetrahydrofuran (100 ml) at 0° C. was added dropwise asolution of borane in tetrahydrofuran (1.0 M, 38.1 ml, 38.1 mmol), andresulting solution was stirred at 0° C. under nitrogen for 30 minutes.Brine (100 ml) was added cautiously to the reaction solution, and theresulting aqueous mixture was extracted with ethyl acetate (2×100 ml).The organic extracts were combined, dried (MgSO₄), filtered, andevaporated under reduced pressure to afford the title compound (III)(4.3 g, 28.1 mmol, 74%) as a white solid: electrospray MS 152 ([M−H]⁺,15).

Preparation 23-(2-Chloropyridin-3-ylmethyl)-3-hydroxy-1-azabicyclo[2.2.2]octaneN-borane Complex (Compound IV)

[0130] A solution of phenyllithium (1.8 M in cyclohexane/ether [7:3],167 ml, 0.3 mol, 3 eq.) was added via a cannula to anhydroustetrahydrofuran (350 ml) at −60° C. under a nitrogen atmosphere. Then,diisopropylamine (0.7 ml, 5 mmol) was added dropwise, followed by adropwise addition of 2-chloropyridine (28.4 ml, 0.3 mol, 3 eq.) over tenminutes. The resulting solution was stirred at −40° C. under nitrogenfor 1.5 hours. The solution was then cooled to −60° C., and a solutionof spiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane]N-borane complex (15.3g, 0.1 mol) in tetrahydrofuran (75 ml) was added dropwise. The resultingreaction mixture was then stirred at −40° C. under nitrogen. After 3hours, a saturated solution of sodium bicarbonate (150 ml) was slowlyadded, followed by water (400 ml), and the resulting aqueous mixture wasallowed to warm to room temperature. The layers were separated and theaqueous phase was extracted with ethyl acetate (3×100 ml). The organiclayers were combined, dried (MgSO₄), filtered, and evaporated underreduced pressure. Column chromatography using silica gel and elutionwith ethyl acetate/hexanes [3:2] afforded the title compound IV as a tansolid (17.5 g, 65.6 mmol, 66%): electrospray MS 269 ([MH]⁺ with ³⁷Cl,10), 267 ([MH]⁺ with ³⁵Cl, 26).

Preparation 3Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (CompoundV)

[0131]3-(2-Chloropyridin-3-ylmethyl)-3-hydroxy-1-azabicyclo[2.2.2]octaneN-borane complex (17.4 g, 65.3 mmol) was dissolved in anhydrousN,N-dimethylformamide (500 ml), the resulting solution was cooled to 0°C. under nitrogen, and a dispersion of sodium hydride (60% in oil, 6.55g, 163 mmol, 2.5 eq.) was added portionwise. The resulting solution wasstirred at room temperature under nitrogen for 16 hours. A saturatedsolution of ammonium chloride (50 ml) was then added at 0° C., followedby ice water (500 ml), and the resulting aqueous mixture was extractedwith chloroform (4×125 mL). The organic extracts were combined, dried(MgSO₄), and evaporated under reduced pressure to afford an orangesolid. Purification through a short column of silica gel eluting withchloroform/acetone [95:5 to 85:15], followed by stirring in hexanes (100ml) and filtration, provided a yellow solid (12.7 g, 55.2 mmol, 84%) ofspiro[1-azabicyclo[2.2.0]octane-3,2′(3′H)-furo[2,3-b]pyridine]N-boranecomplex, electrospray MS 231 ([MH]⁺, 65).Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]N-boranecomplex (12.2 g, 53 mmol) was dissolved in 150 ml of acetone, thesolution was cooled to 0° C., and an aqueous solution of HBr (24%; 50mL) was added. The resulting solution was stirred at room temperatureunder nitrogen for 24 hours. The reaction was concentrated under reducedpressure, and the aqueous residue was treated with saturated aqueoussodium carbonate solution (50 ml). The solution was basified to pH>10using solid sodium carbonate, and the resulting solution was extractedwith chloroform (3×100 ml). The organic extracts were combined, dried(MgSO₄), filtered, and evaporated under reduced pressure to afford thetitle compound VI (11.2 g, 51.8 mmol, 98%, 54% overall) as an off-whitesolid: electrospray MS 217 ([MH]⁺, 72).

[0132] The title compound was separated into its (R)- and(S)-enantiomers by either of the following methods:

[0133] Method A—250 mg of the title compound was separated by chiralHPLC, using a 2 cm×25 cm CHIRALCEL-OD column on a Waters Delta Prep 3000Preparative Chromatography System, eluting with2,2,4-trimethylpentane/ethanol (92:8 to 9:1) at a flow rate of 20ml/min. This provided 111 mg of the (S)-enantiomer ([α]²³=+59.7 (c=1,methanol)) and 90 mg of the (R)-enantiomer ([α]²³=−63.9 (c=1,methanol)).

[0134] Method B—1 g (4.62 mmol) of the title compound was treated withL-(+)-tartaric acid (694 mg; 4.62 mmol) in 15% aqueous ethanol (10 ml)and recrystallized three times to obtain the (S)-enantiomerL-(+)-tartrate (650 mg; 1.77 mmol; [α]²³=+57.7 (c=2, H₂O)). Thefiltrates were concentrated under reduced pressure and the aqueousresidue was basified to pH>10 using solid sodium carbonate. Theresulting mixture was extracted with chloroform (3×25 ml) and thecombined extracts were dried (MgSO₄), and evaporated under reducedpressure. The residue (650 mg; 3 mmol) was treated with D-(−)-tartaricacid (452 mg; 3 mmol) and recrystallized as above to provide the(R)-enantiomer D-(−)-tartrate (775 mg; 2.11 mmol; [α]²³=−58.2° (c=2,H₂O)).

Preparation 4(R)-(−)-5′-Nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](CompoundVI, E═NO₂)

[0135](R)-(−)-Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](3.03 g, 14 mmol) was dissolved in concentrated sulfuric acid (7 ml) at0-5° C., fuming nitric acid (3.3 ml, 70.2 mmol) was added over 10minutes, the mixture was stirred for 1 hour, and heated at 65-70° C. for24 hours, cooled, poured onto ice (200 g), added 300 ml of water,basified to pH 10 with solid potassium carbonate, stirred for 1 hour,filtered off and dried, provided the solid title compound (3.6 g, 13.8mmol, 98%): electrospray MS 262 ([MH]⁺, 100).

Preparation 5(R)-(−)-5′-Aminospiro[1-azabicyclo-[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](Compound VI, E═NH₂)

[0136] A mixture of the enantiomer(R)-(−)-5′-nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](3.8 g, 13.3 mmol) and 10% palladium on carbon (48% water wet, 270 g) inmethanol (90 ml) was hydrogenated for 1 hour at 50 psi of hydrogen. Thecatalyst was filtered off through a pad of celite and the solvent wasevaporated under reduced pressure; the residue was purified by flashchromatography (eluting with ammoniated chloroform/methanol, 95:5 to85:15), provided the title compound (2.5 g, 10.8 mmol, 81%):electrospray MS (m/z, relative intensity) 232 ([MH]⁺, 100).

Preparation 6(R)-(−)-Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-N-oxide](Compound VII)

[0137] A solution of 2.03 g (9.38 mmol) of(R)-(−)-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]in 100 ml of methylene chloride was cooled in an ice bath, to which wasadded 6.90 g (22.8 mmol) of 57-86% m-chloroperbenzoic acid, in portionsover 5 minutes. The reaction was allowed to warm gradually to ambienttemperature and stirred for 24 hours total. The solvent was removed invacuo and the solid residue was dissolved in 100 ml of absolute ethanol,cooled in an ice bath, and sulfur dioxide was bubbled in until thesolution turned cloudy. The reaction was stirred for 4 hours, then thesolvent was removed in vacuo. The solid residue was dissolved in 150 mlof a 9:1 mixture of chloroform and methanol, then extracted with 50 mlof 10% aqueous sodium hydroxide. The organic layer was dried overmagnesium sulfate, concentrated in vacuo and flash chromatographedthrough neutral silica gel using a 9:1 mixture of chloroform and 2.0 Mammonia in methanol as the eluant, giving 1.30 g (60%) of the titlecompound following crystallization from ethyl acetate/hexane (1:1):[α]²³=−56.82 (c=1.09, EtOH), electrospray MS 233 ([MH]⁺, 100).

Preparation 7A5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](Compound VI, E═Br)

[0138] A solution ofspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (100 mg,0.462 mmol) and sodium acetate (410 mg, 5 mmol) in 50% aqueous aceticacid (4 ml) was heated to 60° C. Bromine (0.100 ml, 1.94 mmol) was addedvia a syringe over 10 minutes, and the solution was then heated underreflux for 1 hour. The mixture was allowed to cool to ambienttemperature, basified to pH>10 with sodium carbonate, and extracted withchloroform (3×15 ml). The combined extracts were dried (MgSO₄),filtered, and evaporated under reduced pressure to give the titlecompound (110 mg, 0.37 mmol, 81%) as an off-white solid: electrospray MS295 ([MH]⁺, with ⁷⁹Br, 100), 297 ([MH]⁺, with ⁸¹Br, 98).

Preparation 7B(R)-(−)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](Compound VI, E═Br)

[0139] The enantiomer(R)-(−)-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](1.95 g, 9 mmol) treated in the same way as described in preparation 7Aprovided the title compound (1.77 g, 6 mmol, 67%) ([α]²³=45.5° (c=1,MeOH)).

Example 1R-(−)-5′-N-(Phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0140] Sodium spheres were blotted dry of mineral spirits, weighed (100mg, 4.3 mmol) and added gradually to 2 ml of anhydrous methanol, whilestirring under a nitrogen atmosphere at 0° C. The reaction was stirredat 0° C. for 25 minutes, during which time the vigorous bubbling stoppedand nearly all the solid dissolved.5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine](230 mg, 1.0 mmol) and benzaldehyde (0.23 ml, 1.0 mmol) were added, theice bath was removed, and an additional 2 ml of anhydrous methanol wasadded. The solution was stirred at room temperature for two days, thenheated to 50° C. for 2 hrs. Sodium borohydride (106 mg , 2.8 mmol) wasadded and the reaction was heated at reflux for 90 minutes. Upon coolingto ambient temperature, the methanol was removed in vacuo and theresidue was partitioned between 8 ml of chloroform and 2 ml of water.The aqueous layer was extracted two more times with 8 ml of chloroformand the organic layers were combined and dried over magnesium sulfate.The chloroform was stripped in vacuo, and the crude product was purifiedon a silica flash column using a 0-10% ammoniated methanol/chloroformgradient, giving 0.25 g (77%) of the title compound as a white powder:electrospray MS 322 ([MH]⁺ , 100).

Example 2R-(−)-5′-N-(2-Pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0141] The title compound was prepared by the procedure used in Example1 from 115 mg (0.5 mmol) of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 0.114 ml (1.2 mmol) of 2-pyridine carboxaldehyde to give 84 mg ofthe title compound as a beige powder (52%.): electrospray MS 323 ([MH]⁺,100).

Example 3R-(−)-5′-N-(3-Pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0142] The title compound was prepared by the procedure used in Example1 from 115 mg (0.5 mmol) of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 3-pyridinecarboxaldehyde to give 81 mg, (50%) of the title compoundas a beige powder: electrospray MS 323 ([MH]⁺, 100).

Example 4R-(−)-5′-N-(4-Pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0143] The title compound was prepared by the procedure used in Example1 from 115 mg (0.5 mmol) of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 4-pyridinecarboxaldehyde to give 84 mg, (52%) of the title compoundas a light yellow powder: electrospray MS 323 ([MH]⁺, 100).

Example 5R-(−)-5′-N-(2-Furanylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3b]pyridine]

[0144] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 2-furaldehyde (43 ml, 0.52 mmol), giving 30 mg of the title compoundas a dark yellow semi-solid: electrospray MS 312 ([MH]⁺, 100).

Example 6R-(−)-5′-N-(3-Furanylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0145] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 3-furaldehyde to give 25 mg of the title compound: electrospray MS312 ([MH]⁺, 100).

Example 7R-(−)-5′-N-(2-Thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0146] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 2-thiophenecarboxaldehyde, giving 9 mg of the title compound:electrospray MS 328 ([MH]⁺, 100).

Example 8R-(−)-5′-N-(4-Methoxyphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0147] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 4-methoxybenzaldehyde, providing 18 mg of the title compound:electrospray MS 352 ({MH]⁺, 100).

Example 9R-(−)-5′-N-(4-Chlorophenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0148] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 4-chlorobenzaldehyde to give 62 mg of the title compound:electrospray MS 356 [MH]⁺, ³⁷Cl 358.

Example 10R-(−)-5′-N-(4-Methylphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0149] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 4-tolualdehyde, giving 6 mg of the title compound: electrospray MS336 ([MH]⁺, 100).

Example 11R-(−)-5′-N-(3,4-Dichlorophenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0150] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 3,4-dichlorobenzaldehyde to give 19 mg of the title compound:electrospray MS 390 [MH] ⁺, ³⁷Cl₁ 392, ³⁷Cl₂ 394.

Example 12R-(−)-5′-N-(2-Imidazolylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0151] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 2-imidazolecarboxaldehyde, giving 57 mg of the title compound:electrospray MS 312 ([MH]⁺, 100).

Example 13R-(−)-5′-N-Acetyl-N-(phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0152] Acetic anhydride (25 μl, 0.26 mmol) was added to a solution ofR-(−)-5′-N-(phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine](50 mg, 0.22 mmol) in 1 ml of anhydrous pyridine under nitrogen. Thereaction was heated at 95° C. with an oil bath, then cooled to ambienttemperature and poured into saturated sodium carbonate. The product wasextracted with four portions of chloroform. The organic layers werecombined, dried over magnesium sulfate, and stripped in vacuo. The crudeproduct was passed through a Supelco Visiprep using chloroform and thena 5-15% ammoniated methanol/chloroform gradient. The solvents wereremoved in vacuo, and the purified product was dissolved in methanol andacidified with 0.9 ml of 1.0 M hydrogen chlroride in ether.to provide 59mg (61%) of the title compound as a white semi-solid: electrospray MS364 ([MH]⁺, 100).

Example 14R-(−)-5′-N-Methyl-N-(phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0153] Under a nitrogen atmosphere, sodium cyanoborohydride (39 mg, 0.62mmol) was added to a solution of 50 mg, (0.22 mmol) ofR-(−)-5′-N-(phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 165 μl (2.2 mmol) of 37% aqueous formaldehyde in 1 ml of deionizedwater adjusted to pH 3 using concentrated hydrochloric acid. Thereaction was stirred at room temperature, adding acid to adjust the pHwhenever it rose above 6. After one hour, the reaction was poured intosaturated sodium carbonate and this was extracted with four portions ofchloroform. The organic layers were combined, dried over magnesiumsulfate, and stripped in vacuo. The residue was passed through a SupelcoVisiprep using an ammoniated methanol/chloroform gradient. The solventswere removed in vacuo, and residue was taken up in methanol andacidified with 0.9 ml of 1.0 M hydrogen chloride in ether. Removal ofthe solvent in vacuo gave 64 mg (98%) of the HCl salt of the titlecompound as a light yellow semi-solid: electrospray MS 336 ([MH]⁺, 100).

Example 15(R)-(−)-5′-N-(3-Pyridylamino)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

[0154] In a pressure tube sealed under nitrogen,(R)-(−)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](105.1 mg, 0.36 mmol), 3-aminopyridine (69 mg, 0.73 mmol),tris(dibenzylidineacetone)dipalladium (0) (21 mg, 0.023 mmol),racemic-2-2′-bis(diphenylphosphino)1,1′-binaphthyl (34mg, 0.055 mmol),sodium t-butoxide (0.105 g, 1.09 mmol), and 1,2-dimethoxyethane (5 ml)were heated and stirred at 100° C. After 3 days the solution was allowedto cool, and partitioned between water and chloroform. The chloroformlayer was then dried by addition of magnesium sulfate and filteredthrough a solid phase extraction cartridge containing 5 g silica. Thecrude product was eluted from the cartridge with a 1:1 v/v mixture ofmethanolic ammonia and chloroform; the resulting solution wasevaporated. The residue was purified by reverse phase HPLC on a C-18column using a gradient of 0-50% acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluant. The product-containing fractionswere evaporated and the product was dissolved in a small volume ofmethanol (ca. 5 ml), and excess hydrogen chloride (1 M solution inether, appr. 5 ml) was added. The solution was re-evaporated to give thetitle compound (54 mg, 0.13 mmol) as a hydrochloride salt: electrosprayMS 309 ([MH]⁺, 100); [α]₅₈₉ nm═−42.0 (c=0.1, MeOH).

Example 16R-(−)-6′-N-(Phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0155](R)-(−)-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-N-oxide](VII) [970 mg (4.20 mmol)] was dissolved in 10 ml of phosphorusoxychloride, while stirring in an ice bath. The suspension was thenheated to reflux and stirred for 5 hours. Upon cooling to ambienttemperature, the reaction was poured onto 100 g of ice, diluted with 100ml of water, made basic with potassium carbonate, and extracted withchloroform (3×50 ml). The combined organic extract was dried overanhydrous magnesium sulfate, concentrated in vacuo, and flashchromatographed through neutral silica gel using a 95:5 mixture ofchloroform and 2.0N ammonia in methanol to give 700 mg of(R)-(−)-6-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]as an off white solid.

[0156] A solution of 85 mg (0.34 mmol) of the chloride in 3.0 ml ofbenzylamine was heated to reflux, under a nitrogen atmosphere, for 23hours. Upon cooling to ambient temperature, the solution was flashchromatographed through neutral silica gel using a 9:1 mixture ofchloroform and 2.0N ammonia in methanol, providing 22 mg (20%) of thetitle compound, electrospray MS 322 ([MH]⁺, 100).

Example 17R-(−)-5′-N-(3-Thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0157] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 3-thiophenecarboxaldehyde, giving 61 mg (85%) of the title compound:electrospray MS 328 ([MH]⁺, 100).

Example 18R-(−)-5′-N-(2-Phenylethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0158] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and phenylacetaldehyde, giving 31 mg of the title compound: electrosprayMS 336 ([MH]⁺, 100).

Example 19R-(−)-5′-N-(3-Phenylpropyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0159] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 3-phenylpropionaldehyde, giving 42 mg of the title compound:electrospray MS 350 ([MH]⁺, 100).

Example 20R-(−)-5′-N-(Quinolin-3-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0160] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 3-quinolinecarboxaldehyde, giving 47 mg of the title compound:electrospray MS 373 ([MH]⁺, 100).

Example 21R-(−)-5′-N-(Quinolin-4-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0161] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 4-quinolinecarboxaldehyde, giving 3 mg of the title compound:electrospray MS 373 ([MH]⁺, 100).

Example 22R-(−)-5′-N-(1,4-Benzodioxan-6-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0162] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 1,4-benzodioxan-6-ylcarboxaldehyde, giving 31 mg of the titlecompound: electrospray MS 380 ([MH]⁺, 100).

Example 23R-(−)-5′-N-(Imidazol-4-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0163] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 4(5)-imidazolecarboxaldehyde, giving 1 mg of the title compound:electrospray MS 312 ([MH]⁺, 100).

Example 24R-(−)-5′-N-(trans-3-pyridinylprop-2-enyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0164] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and cinnamaldehyde, giving 43 mg of the title compound: electrospray MS348 ([MH]⁺, 100).

Example 25R-(−)-5′-N-(Thiazol-2-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0165] The title compound was prepared by the procedure used in Example1 from 50 mg (0.22 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 2-thiazolecarboxaldehyde, giving 13 mg of the title compound:electrospray MS 329 ([MH]⁺, 100).

Example 26R-(−)-5′-N-(3-Methylphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0166] Titanium tetrachloride (0.5 ml of a 1.0 M solution indichloromethane) was added to a solution of 50 mg (0.22 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine],0.066 ml (0.47 mmol) of triethylamine and 0.026 ml (0.22 mmol) ofm-tolualdehyde in 2 ml of chloroform, under a nitrogen atmosphere. Afterstirring for 16 h, a solution of 0.65 mmol of sodium cyanoborohydride in0.55 ml of methanol was added; the resulting solution was stirred for 20min, then poured into 20 ml of aqueous sodium carbonate and extractedwith chloroform (4×10 ml). The combined organic extract was dried overmagnesium sulfate, concentrated in vacuo and flash chromatographedthrough neutral silica gel using a 0-15% ammoniated methanol/chloroformgradient, giving 60 mg (81%) of the title compound: electrospray MS 336([MH]⁺, 100).

Example 27R-(−)-5′-N-(2-Chlorophenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0167] The title compound was prepared by the procedure used in Example26 from 50 mg (0.22 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 2-chlorobenzaldehyde, giving 63 mg of the title compound:electrospray MS 356 ([MH]⁺, 100).

Example 28R-(−)-5′-N-(3-Chlorophenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0168] The title compound was prepared by the procedure used in Example26 from 50 mg (0.22 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 2-chlorobenzaldehyde, giving 50 mg of the title compound:electrospray MS 356 ([MH]⁺, 100).

Example 29R-(−)-5′-N-(3-Phenylpropynyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0169] The title compound was prepared by the procedure used in Example26 from 400 mg (1.76 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 3-phenylpropargyl aldehyde, giving 212 mg of the title compound:electrospray MS 346 ([MH]⁺, 100).

Example 30R-(−)-5′-N-(3-Hydroxyphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0170] The title compound was prepared by the procedure used in Example26 from 250 mg (1.10 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 3-hydroxybenzaldehyde, giving 117 mg of the title compound:electrospray MS 338 ([MH]⁺ , 100).

Example 31R-(−)-5′-N-(4-Hydroxyphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0171] The title compound was prepared by the procedure used in Example26 from 250 mg (1.10 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 4hydroxybenzaldehyde, giving 31 mg of the title compound:electrospray MS 338 ([MH]⁺, 100).

Example 32R-(−)-5′-N-[trans-3-(4-Pyridinyl)prop-2-enyl]aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0172] The title compound was prepared by the procedure used in Example26 from 250 mg (1.10 mmol) ofR-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and trans-3-pyridylpropenal, giving 77 mg of the title compound:electrospray MS 349 ([MH]⁺, 100).

Example 33R-(−)-5′-N-Acetyl-N-(3-thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0173] The title compound was prepared by the procedure used in Example13 from 100 mg ofR-(−)-5′-N-(3-thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and acetic anhydride, giving 25 mg of the title compound: electrosprayMS 370 ([MH]⁺, 100).

Example 34R-(−)-5′-N-Methyl-N-(4-pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0174] The title compound was prepared by the procedure used in Example14 from 100 mg ofR-(−)-5′-N-(4-pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 37% aqueous formaldehyde, giving 26 mg of the title compound:electrospray MS 337 ([MH]⁺, 100).

Example 35R-(−)-5′-N-Methyl-N-(3-pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0175] The title compound was prepared by the procedure used in Example14 from 200 mg ofR-(−)-5′-N-(3-pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and 37% aqueous formaldehyde, giving 190 mg of the title compound:electrospray MS 337 ([MH]⁺, 100).

Example 36R-(−)-5′-N-(2-Hydroxyethyl)-N-(3-thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]

[0176] The title compound was prepared by the procedure used in Example14 from 100 mg ofR-(−)-5′-N-(3-thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine]and glyoxal, giving 54 mg of the title compound: electrospray MS 372([MH]⁺, 100).

1. A compound of formula I,

wherein NRR₁ is attached at the 5- or 6-position of the furopyridinering; R is hydrogen, C₁-C₄ alky, or COR₂; R₁ is (CH₂)_(n)Ar, CH₂CH═CHAr,or CH₂C≡CAr; n is 0 to 3; A is N or NO; Ar is a 5- or 6-memberedaromatic or heteroaromatic ring which contains zero to four nitrogenatoms, zero to one oxygen atoms, and zero to one sulfur atoms; or: an8-, 9- or 10-membered fused aromatic or heteroaromatic ring systemcontaining zero to four nitrogen atoms, zero to one oxygen atoms, andzero to one sulfur atoms; any of which may optionally be substitutedwith one to two substitutents independently selected from: halogen,trifluoromethyl, or C₁-C₄ alkyl; R₂ is hydrogen, C₁-C₄ alkyl; C₁-C₄alkoxy; or phenyl ring optionally substituted with one to three of thefollowing substituents: halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, OH, OC₁-C₄ alkyl, CO₂R₅, —CN, —NO₂, —NR₃R₄, or —CF₃; R₃, R₄ andR₅ are independently hydrogen; C₁-C₄ alkyl; or phenyl ring optionallysubstituted with one to three of the following substituents: halogen,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, OH, OC₁-C₄ alkyl, —CN; —NO₂,or —CF₃; or an enantiomer thereof, and pharmaceutically acceptable saltsthereof.
 2. A compound according to claim 1, wherein A is N; or anenantiomer thereof, and pharmaceutically acceptable salts thereof.
 3. Acompound according to claim 1 or 2, wherein R₁ is (CH₂)_(n)Ar; or anenantiomer thereof, and pharmaceutically acceptable salts thereof.
 4. Acompound according to claim 1 or 2, wherein R₁ is CH₂CH═CHAr; or anenantiomer thereof, and pharmaceutically acceptable salts thereof.
 5. Acompound according to claim 1 or 2, wherein R₁ is CH₂C≡CAr; or anenantiomer thereof, and pharmaceutically acceptable salts thereof.
 6. Acompound according to any one of claims 1 to 5, wherein Ar is selectedfrom the group: phenyl ring optionally substituted with one to three ofthe following substituents: halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, OH, OC₁-C₄ alkyl, CO₂R₅, —CN, —NO₂, —NR₃R₄, and —CF₃; 2-, 3-,or 4-pyridyl; 2-, or 3-furanyl; 2-, or 3-thienyl; 2-, or 4-imidazolyl;1, 2-, or 3-pyrrolyl; 2-, or 4-oxazolyl; and 3-, or 4-isoxazolyl; or anenantiomer thereof, and pharmaceutically acceptable salts thereof.
 7. Acompound according to any one of claims 1 to 5, wherein Ar is selectedfrom the group: 1-, or 2-naphthyl; 2-, 3-, 4-, 5-, 6-, 7-, or8-quinolyl; 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl; 2-, 4-, 5-, 6-, or7-benzoxazolyl; and 3-, 4-, 5-, 6-, or 7-benzisoxazolyl; or anenantiomer thereof, and pharmaceutically acceptable salts thereof.
 8. Acompound according to any one of claims 1 to 6, wherein R₃, R₄ and R₅are independently hydrogen, or C₁-C₄ alkyl; or an enantiomer thereof,and pharmaceutically acceptable salts thereof.
 9. A compound accordingto any one of claims 1 to 8, wherein n is
 1. 10. A compound according toany one of claims 1 to 8, wherein R is hydrogen.
 11. A compoundaccording to any one of claims 1 to 8, wherein Ar is an heteroaromaticring.
 12. A compound according to any one of claims 1 to 8 wherein n is1; R is hydrogen and Ar is an heteroaromatic ring.
 13. A compoundaccording to claim 1, said compound being:R-(−)-5′-N-(Phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-(2-Pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-(3-Pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-(4-Pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-(2-Furanylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-(3-Furanylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-(2-Thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-(2-Imidazolylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(4-Methoxyphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(4-Chlorophenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(4-Methylphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(3,4-Dichlorophenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-Acetyl-N-(phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-Methyl-N-(phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];(R)-(−)-5′-N-(3-Pyridyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(R)-(−)-6′-N-(Phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(3-Thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(2-Phenylethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(3-Phenylpropyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(Quinolin-3-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(Quinolin-4-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(1,4-Benzodioxan-6-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(Imidazol-4-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(trans-3-Phenylprop-2-enyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(Thiazol-2-ylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(3-Methylphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(2-Chlorophenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(3-Chlorophenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(3-Phenylpropynyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(3-Hydroxyphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(4-Hydroxyphenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-[trans-3-(4-Pyridinyl)prop-2-enyl]aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-Acetyl-N-(3-Thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-Methyl-N-(4-pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-Methyl-N-(3-pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-N-(2-Hydroxyethyl)-N-(3-thienylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];or an enantiomer thereof, and pharmaceutically acceptable salts thereof.14. A compound according to claim 1, said compound being:R-(−)-5′-(3-Pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];R-(−)-5′-(4-Pyridylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];or an enantiomer thereof, and pharmaceutically acceptable salts thereof.15. A compound according to any one of claims 1 to 14 for use intherapy.
 16. A pharmaceutical composition including a compound asdefined in any one of claims 1 to 14, in admixture with an inertpharmaceutically acceptable diluent or carrier.
 17. The pharmaceuticalcomposition according to claim 16, for use in the treatment orprophylaxis of psychotic disorders or intellectual impairment disorders.18. The pharmaceutical composition according to claim 16, for use in thetreatment or prophylaxis of human diseases or conditions in whichactivation of the α7 nicotinic receptor is beneficial.
 19. Thepharmaceutical composition according to claim 16, for use in thetreatment or prophylaxis of Alzheimer's disease, learning deficit,cognition deficit, attention deficit, memory loss, Attention DeficitHyperactivity Disorder, Lewy Body Dementia, anxiety, schizophrenia,mania or manic depression, Parkinson's disease, Huntington's disease,Tourette's syndrome, neurodegenerative disorders in which there is lossof cholinergic synapse, jetlag, cessation of smoking, nicotine addictionincluding that resulting from exposure to products containing nicotine,pain, or ulcerative colitis.
 20. The pharmaceutical compositionaccording to claim 19, for use in the treatment or prophylaxis ofAlzheimer's disease, learning deficit, cognition deficit, attentiondeficit, Lewy Body Dementia, memory loss or Attention DeficitHyperactivity Disorder.
 21. The pharmaceutical composition according toclaim 19, for use in the treatment or prophylaxis of anxiety,schizophrenia, mania or manic depression.
 22. The pharmaceuticalcomposition according to claim 19, for use in the treatment orprophylaxis of Parkinson's disease, Huntington's disease, Tourette'ssyndrome, or neurodegenerative disorders in which there is loss ofcholinergic synapses.
 23. The pharmaceutical composition according toclaim 19, for use in the treatment or prophylaxis of jetlag, nicotineaddiction including that resulting from exposure to products containingnicotine, pain, or ulcerative colitis.
 24. The pharmaceuticalcomposition according to claim 19, for use in the treatment orprophylaxis of Alzheimer's disease.
 25. Use of a compound as defined inany one of claims 1 to 14, in the manufacture of a medicament for thetreatment or prophylaxis of psychotic disorders or intellectualimpairment disorders.
 26. The use of a compound as defined in any one ofclaims 1 to 14, in the manufacture of a medicament for the treatment orprophylaxis of human diseases or conditions in which activation of theα7 nicotinic receptor is beneficial.
 27. The use according to claim 25or claim 26, wherein the condition or disorder is Alzheimer's disease,learning deficit, cognition deficit, attention deficit, memory loss,Attention Deficit Hyperactivity Disorder, Lewy Body Dementia, anxiety,schizophrenia, mania or manic depression, Parkinson's disease,Huntington's disease, Tourette's syndrome, neurodegenerative disordersin which there is loss of cholinergic synapse, jetlag, cessation ofsmoking, nicotine addiction including that resulting from exposure toproducts containing nicotine, pain, or ulcerative colitis.
 28. The useaccording to claim 27, wherein the condition or disorder is Alzheimer'sdisease, learning deficit, cognition deficit, attention deficit, LewyBody Dementia, memory loss or Attention Deficit Hyperactivity Disorder.29. The use according to claim 27, wherein the condition or disorder isanxiety, schizophrenia, mania or manic depression.
 30. The use accordingto claim 27, wherein the condition or disorder is Parkinson's disease,Huntington's disease, Tourette's syndrome, or neurodegenerativedisorders in which there is loss of cholinergic synapses.
 31. The useaccording to claim 27, wherein the condition or disorder is jetlag,nicotine addiction including that resulting from exposure to productscontaining nicotine, pain, or ulcerative colitis.
 32. The use accordingto claim 27, wherein the condition or disorder is Alzheimer's disease.33. A method of treatment or prophylaxis of psychotic disorders orintellectual impairment disorders, which comprises administering atherapeutically effective amount of a compound as defined in any one ofclaims 1 to
 14. 34. A method of treatment or prophylaxis of humandiseases or conditions in which activation of the α7 nicotinic receptoris beneficial, which comprises administering a therapeutically effectiveamount of a compound as defined in any one of claims 1 to
 14. 35. Themethod according to claim 33 or claim 34, wherein the condition ordisorder Alzheimer's disease, learning deficit, cognition deficit,attention deficit, memory loss, Attention Deficit HyperactivityDisorder, Lewy Body Dementia, anxiety, schizophrenia, mania or manicdepression, Parkinson's disease, Huntington's disease, Tourette'ssyndrome, neurodegenerative disorders in which there is loss ofcholinergic synapse, jetlag, cessation of smoking, nicotine addictionincluding that resulting from exposure to products containing nicotine,pain, or ulcerative colitis.
 36. The method according to claim 33 orclaim 34, wherein the condition or disorder is Alzheimer's disease,learning deficit, cognition deficit, attention deficit, Lewy BodyDementia, memory loss or Attention Deficit Hyperactivity Disorder. 37.The method according to claim 33 or claim 34, wherein the condition ordisorder is anxiety, schizophrenia, mania or manic depression.
 38. Themethod according to claim 33 or claim 34, wherein the condition ordisorder is Parkinson's disease, Huntington's disease, Tourette'ssyndrome, or neurodegenerative disorders in which there is loss ofcholinergic synapses.
 39. The method according to claim 33 or claim 34,wherein the condition or disorder is jetlag, nicotine addictionincluding that resulting from exposure to products containing nicotine,pain, or ulcerative colitis.
 40. The method according to claim 33 orclaim 34, wherein the condition or disorder is Alzheimer's disease. 41.A process for preparing a compound of formula I, as defined in any oneof claims 1 to 14, or an enantiomer thereof, and pharmaceuticallyacceptable salts thereof, which comprises a) for preparing compoundswherein NRR1 is positioned in the 5′-position, alkylating or acylatingcompounds of formula VI, wherein E is halogen, NO₂, or NHR, in asuitable solvent:

or b) for preparing compounds wherein NRR1 is positioned in the5′-position, reacting compounds of formula VI, wherein E is halogen,NO₂, or NHR, with an amine in the presence of a suitable organometalliccatalyst, base and solvent:

or c) for preparing compounds wherein NRR1 is positioned in the6′-position, reacting compounds of formula VII, with a halogenatingreagent, followed by reaction with an amine in an inert solvent:

or d) for preparing compounds wherein NRR1 is positioned in the6′-position, oxidising compounds of formula VIII or IX with a peroxidicreagent in a suitable solvent, followed by partial reduction.
 42. Acompound of the formula


43. A compound of the formula

where E is NO₂, NHR, or halogen.